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Neural transplants for parkinson’s disease: what are the issues?

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Poiesis & Praxis

Abstract

Parkinson’s disease (PD) is a common neurodegenerative disorder of the nervous system that affects about 1 in 800 people and for which we have symptomatic but not curative therapies. At the core of the disease is the loss of a specific population of dopaminergic neurons within the brain, and replacement of dopamine through drug therapies has provided clinically significant benefit for many patients. However this therapy only ever offers a temporary amelioration of symptoms and with time this symptomatic therapy becomes less efficacious and produces its own unique side-effects. As a result more effective curative therapies have been sought, including the use of cell based therapies to replace the lost dopaminergic neurons. In this review I am going to discuss PD and its possible repair using neural transplants. In particular I am going to discuss which type of cells are best considered as a reparative therapy, where they should be transplanted in the brain, when in the disease course and in which type of patient. By considering these issues, I hope to be able to make some recommendations as to the future use of this approach in PD.

Zusammenfassung

Morbus Parkinson (MP) ist eine verbreitete neurodegenerative Erkrankung des Nervensystems, die etwa einen unter 800 Menschen befällt und für die nur symptomatische, aber keine heilenden Therapien bekannt sind. Den Kern der Krankheit bildet der Verlust einer spezifischen Population dopaminerger Neuronen innerhalb des Gehirns. Dopaminersatz durch Medikationen hat daher bei vielen Patienten klinisch signifikanten Nutzen gezeigt. Solche Therapie bietet jedoch nur vorübergehende Linderung von Symptomen, und mit der Zeit verliert diese symptomatische Therapie immer mehr an Wirksamkeit und ruft ihre eigenen spezifischen Nebenwirkungen hervor. Folglich sucht man nach effektiveren kurativen Therapien, darunter auch Zelltherapien, zur Ersetzung der verlorenen dopaminergen Neuronen. In diesem Übersichtsartikel werden MP und seine mögliche Behebung mittels neuraler Transplantate diskutiert. Insbesondere wird darauf eingegangen, welche Zelltypen am besten als reparative Therapiezellen in Betracht gezogen werden sollten, wo im Gehirn sie zu transplantieren wären, in welcher Phase der Krankheit und bei welchem Patiententyp. Ziel dieser Betrachtungen ist die mögliche Formulierung von Empfehlungen hinsichtlich der zukünftigen Nutzung dieses Therapieansatzes für MP.

Résumé

La maladie de Parkinson (MP) est une affection neurodégénérative très répandue du système nerveux, qui touche environ une personne sur 800 et pour laquelle existent des traitements symptomatiques, mais pas de traitements curatifs. Au cœur de la maladie, il y a la disparition d’une population spécifique de neurones dopaminergiques dans le cerveau. Le remplacement médicamenteux de la dopamine s’est par conséquent avéré très bénéfique du point de vue clinique pour de nombreux patients. De telles thérapies n’apportent toutefois qu’un apaisement passager des symptômes, et la thérapie symptomatique perd de plus en plus de son efficacité avec le temps, et finit par ne plus provoquer que ses propres effets secondaires. On recherche par conséquent des thérapies curatives plus efficaces, dont des thérapies cellulaires visant à remplacer les neurones dopaminergiques détruits. Cet article récapitulatif se penche sur la MP et les réparations éventuellement possibles au moyen de transplants neuraux. Il s’interroge en particulier sur les types de cellules pouvant être envisagés pour une thérapie cellulaire réparatrice, sur le lieu de transplantation dans le cerveau, sur la phase de la maladie indiquée pour cette intervention et sur le type de patients approprié. Le but de ces observations est de formuler certaines recommandations sur l’utilisation future de cette approche de la MP.

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References

  • Armstrong RJE, Jain M, Barker RA (2001) Stem cell transplantation as an approach to brain repair Exp Opin Ther Patent 11:1563–1582

    Article  Google Scholar 

  • Armstrong RJE, Barker RA (2001) An hypothesis: Neurodegeneration: a failure of neuroregeneration? Lancet 358:1174–1176

    Article  Google Scholar 

  • Barker RA, Dunnett SB (1999) Neural repair, transplantation and rehabilitation. Psychology Press, Hove

    Google Scholar 

  • Barker RA (2002) Repairing the brain in Parkinson’s disease---where next? Movement Disord 17:233–241

    Article  Google Scholar 

  • Barker RA (2000) Porcine neural xenografts: What are the issues? Novartis Symp. Found 231:184–201

    Article  Google Scholar 

  • Barker RA, Ratcliffe E, McLaughlin M, Richards A, Dunnett SB (2000) A role for complement in the rejection of porcine ventral mesencephalic xenografts in a rat model of Parkinson’s disease. J Neurosci 20:3415–3424

    Google Scholar 

  • Barker RA, Jain M, Armstrong RJE, Caldwell MA (2003) Stem cells and neurological disease. J Neurol Neurosurg Psychiatry 74:553–557

    Article  Google Scholar 

  • Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415–455

    Article  Google Scholar 

  • Bezard E, Brotchie JM, Gross CE (2001) Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nat Rev Neurosci 2:577–588

    Article  Google Scholar 

  • Björklund A, Dunnett S, Brundin P, Stoessl AJ, Freed CR, Breeze RE, Levivier M, Peschanski M, Studer L, Barker RA (2003) Neural transplantation for the treatment of Parkinson’s disease. Lancet Neurol 2:437–445

    Article  Google Scholar 

  • Björklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. PNAS 99:2344–2349

    Article  Google Scholar 

  • Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol 249(3 Suppl):III/1–III/5

    Article  Google Scholar 

  • Brecknell JE, Du JS, Muir E, Fidler PS, Hlavin ML, Dunnett SB, Fawcett JW (1996) Bridge grafts of fibroblast growth factor-4-secreting schwannoma cells promote functional axonal regeneration in the nigrostriatal pathway of the adult rat. Neuroscience 74:775–784

    Article  Google Scholar 

  • Cotzias GC, Van Woert MH, Schiffer LM (1967) Aromatic amino acids and modification of parkinsonism. New Eng J Med 276:374–379

    Article  Google Scholar 

  • Dewey RB Jr (2004) Autonomic dysfunction in Parkinson’s disease. Neurol Clin 22(3 Suppl):S127–S139

    Article  Google Scholar 

  • Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ (2003) Tremor in Parkinson’s disease and serotonergic dysfunction: an 11C-WAY 100635 PET study. Neurology 60:601–605

    Article  Google Scholar 

  • Dunnett SB, Björklund A, Lindvall O (2001) Cell therapy in Parkinson’s disease---stop or go? Nat Rev Neurosci 2:365–369

    Article  Google Scholar 

  • Fenelon G, Mahieux F, Huon R, Ziegler M (2000) Hallucinations in Parkinson’s disease. Prevalence, phenomenology and risk factors. Brain 123:733–745

    Article  Google Scholar 

  • Foltynie T, Brayne C, Barker RA (2002) The heterogeneity of Parkinson’s disease---a review. J Neurol 249:138–145

    Article  Google Scholar 

  • Foltynie T, Robbins TW, Brayne C, Barker RA (2004a) Cognitive impairments are common among a population cohort of newly diagnosed PD patients---the CamPaIGN study. Brain 127:550–560

    Article  Google Scholar 

  • Foltynie T, Goldberg TE, Lewis SG et al. (2004b) Planning ability in Parkinson’s disease is influenced by the COMT Val158Met polymorphism. Mov Disord 19:885–891

    Article  Google Scholar 

  • Foltynie T, Goldberg TE, Lewis SJG, Blackwell AD, Kolachana B, Weinberger DR, Robbins TW, Barker RA (2005) The BDNF Val66Met functional polymorphism has a gender specific influence on planning ability in Parkinson’s disease. J Neurol 252:833–838

    Article  Google Scholar 

  • Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. New Eng J Med 344:710–719

    Article  Google Scholar 

  • Gill SS, Patel NK, Hotton GR, O’Sullivan K, McCarter R, Bunnage M, Brooks DJ, Svendsen CN, Heywood P (2003) Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 9:589–595

    Article  Google Scholar 

  • Hagell P, Piccini P, Björklund A, Brundin P, Rehncrona S, Widner H, Crabb L, Pavese N, Oertel WH, Quinn N, Brooks DJ, Lindvall O (2002) Dyskinesias following neural transplantation in Parkinson’s disease. Nat Neurosci 5:627–628

    Google Scholar 

  • Jain M, Armstrong RJE, Tyers P, Rosser AE, Barker RA (2003) GABAergic immunoreactivity is predominant in neurons derived from expanded human neural precursor cells in vitro. Exp Neurol 182:113–123

    Article  Google Scholar 

  • Katzenschlager R, Hughes A, Evans A, Manson AJ, Hoffman M, Swinn L, Watt H, Bhatia K, Quinn N, Lees AJ (2005) Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson’s disease: a prospective study using single-dose challenges. Mov Disord. 20:151–157

    Article  Google Scholar 

  • Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418:50–56

    Article  Google Scholar 

  • Kish SJ, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. Pathophysiologic and clinical implication. New Eng J Med 318:876–880

    Article  Google Scholar 

  • Kordower JH, Freeman TB, Olanow CW (1998) Neuropathology of fetal nigral grafts in patients with Parkinson’s disease. Mov Disord 13(Suppl1):88–95

    Google Scholar 

  • Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, McBride J, Chen EY, Palfi S, Roitberg BZ, Brown WD, Holden JE, Pyzalski R, Taylor MD, Carvey P, Ling Z, Trono D, Hantraye P, Deglon N, Aebischer P (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290:767–773

    Article  Google Scholar 

  • Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD, Benazzouz A, LeBas JF, Benabid AL, Pollak P (2003) Five year follow up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. New Engl J Med 349:1925–1934

    Article  Google Scholar 

  • Kuan W-L, Barker RA (2005) New therapeutic approaches to Parkinson’s disease including neural transplants. Neurorehabil Neural Repair 19:155–181

    Article  Google Scholar 

  • Lang AE, Lozano AM (1998) Parkinson’s disease. New Engl J Med 339:1044–1053, 1130–1143

    Google Scholar 

  • Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD (2000) Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 18:675–679

    Article  Google Scholar 

  • Lewis SJ, Dove A, Robbins TW, Owen AM, Barker RA (2003) Cognitive impairments in early Parkinson’s disease are accompanied by reductions in activity in frontostriatal neural circuitry. J Neurosci 23:6351–6356

    Google Scholar 

  • Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA (2005) Heterogeneity of Parkinson’s disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 76:343–348

    Article  Google Scholar 

  • Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B, Frackowiak R, et al. (1990) Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247:574–577

    Article  Google Scholar 

  • Lindvall O, Sawle G, Widner H, Rothwell JC, Björklund A, Brooks D, et al. (1994) Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann Neurol 35:172–180

    Article  Google Scholar 

  • Love S, Plaha P, Patel NK, Hotton GR, Brooks DJ, Gill SS (2005) Glial cell line-derived neurotrophic factor induces neuronal sprouting in human brain. Nat Med 11:703–704

    Article  Google Scholar 

  • Ma Y, Feigin A, Dhawan V, Fukuda M, Shi Q, Greene P, Breeze R, Fahn S, Freed C, Eidelberg D (2002) Dyskinesia after fetal cell transplantation for parkinsonism: a PET study. Ann Neurol 52:628–634

    Article  Google Scholar 

  • Nikkhah G, Olsson M, Eberhard J, Bentlage C, Cunningham MG, Björklund A (1994) A microtransplantation approach for cell suspension grafting in the rat Parkinson model: a detailed account of the methodology. Neuroscience 63:57–72

    Article  Google Scholar 

  • Nutt JG, Burchiel KL, Comella CL, Jankovic J, Lang AE, Laws ER Jr, Lozano AM, Penn RD, Simpson RK Jr, Stacy M, Wooten GF, ICV GDNF Study Group (2003) Implanted intracerebroventricular. Glial cell line-derived neurotrophic factor. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60:69–73

    Article  Google Scholar 

  • Olanow CW, Hauser RA, Gauger L, Malapira T, Koller W, Hubble J, Bushenbark K, Lilienfeld D, Esterlitz J (1995) The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol 38:771–777

    Article  Google Scholar 

  • Olanow CW, Goetz C, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 54:403–414

    Article  Google Scholar 

  • Paradis K, Langford G, Long Z, Heneine W, Sandstrom P, Switzer WM, Chapman LE, Lockey C, Onions D, Otto E (1999) Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group. Science 285:1236–41

    Article  Google Scholar 

  • Patel NK, Bunnage M., Plaha P, Svendsen CN, Heywood P, Gill SS (2005) Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol 57:298–302

    Article  Google Scholar 

  • Piccini P, Brooks DJ, Björklund A, Gunn RN, Grasby PM, Rimoldi O, Brundin P, Hagell P, Rehncrona S, Widner H, Lindvall O (1999) Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nat Neurosci 2:1137–1140

    Article  Google Scholar 

  • Piccini P, Lindvall O, Björklund A, Brundin P, Hagell P, Ceravolo R, Oertel W, Quinn N, Samuel M, Rehncrona S, Widner H, Brooks DJ (2000) Delayed recovery of movement-related cortical function in Parkinson’s disease after striatal dopaminergic grafts. Ann Neurol 48:689–695

    Article  Google Scholar 

  • Piccini P, Pavese N, Hagell P, Reimer J, Björklund A, Oertel WH, Quinn NP, Brooks DJ, Lindvall O (2005) Factors affecting the clinical outcome after neural transplantation in Parkinson’s disease. Brain 128:2977–2986

    Article  Google Scholar 

  • Rakshi JS, Uema T, Ito K, Bailey DL, Morrish PK, Ashburner J, Dagher A, Jenkins IH, Friston KJ, Brooks DJ (1999) Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson’s disease. A 3D [18(F)]dopa-PET study. Brain 122:1637–1650

    Article  Google Scholar 

  • Reynolds BA, Tetzlaff W, Weiss S (1992) A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12:4565–74

    Google Scholar 

  • Ross GW, Petrovitch H, Abbott RD, Nelson J, Markesbery W, Davis D, Hardman J, Launer L, Masaki K, Tanner CM, White LR (2004) Parkinsonian signs and substantia nigra neuron density in decendents elders without PD. Ann Neurol 56:532–9

    Article  Google Scholar 

  • Sawle GV, Bloomfield PM, Björklund A, Brooks DJ, Brundin P, Leenders KL, et al. (1992) Transplantation of fetal dopamine neurons in Parkinson’s disease: PET [18F]6-L-fluorodopa studies in two patients with putaminal implants. Ann Neurol 31:166–173

    Article  Google Scholar 

  • Singaram C, Ashraf W, Gaumnitz EA, Torbey C, Sengupta A, Pfeiffer R, Quigley EM (1995) Dopaminergic defect of enteric nervous system in Parkinson’s disease patients with chronic constipation. Lancet 346:861–864

    Article  Google Scholar 

  • van der Laan LJ, Lockey C, Griffeth BC, Frasier FS, Wilson CA, Onions DE, Hering BJ, Long Z, Otto E, Torbett BE, Salomon DR (2000) Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice. Nature 407:90–94

    Article  Google Scholar 

  • Whone AL, Moore RY, Piccini PP, Brooks DJ (2003) Plasticity of the nigropallidal pathway in Parkinson’s disease. Ann Neurol 53:206–13

    Article  Google Scholar 

  • Wictorin K, Bundin P, Sauer H, Lindvall O, Björklund A (1992) Long distance directed axonal growth from human dopaminergic mesencephalic neuroblasts implanted along the nigrostriatal pathway in 6-hydroxydopamine lesioned adult rats. J Comp Neurol 323:475–494

    Article  Google Scholar 

  • Yip S, Aboody KS, Burns M, Imitola J, Boockvar JA, Allport J, Park KI, Teng YD, Lachyankar M, McIntosh T, O’Rourke DM, Khoury S, Weissleder R, Black PM, Weiss W, Snyder EY (2003) Neural stem cell biology may be well suited for improving brain tumor therapies. Cancer J 9:189–204

    Article  Google Scholar 

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Acknowledgements

I would like to thank those within my research group who have provided insights and experimental/clinical work to support the views put forward in this review. In addition I would like to thank my collaborators especially Dr Adrian Owen and Professors Robbins, Sahakian and Weinberger. Finally I would like to the sponsors of our work namely the Medical Research Council, The Parkinson’s Disease Society of the UK and the Wellcome Trust. Finally I would like to thank all the patients and their families who have contributed to all of our clinical research.

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  1. Cambridge Centre for Brain Repair, Forvie Site Robinson Way, CB2 2PY, Cambridge, UK

    Roger A. Barker

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Barker, R.A. Neural transplants for parkinson’s disease: what are the issues?. Poiesis Prax 4, 129–143 (2006). https://doi.org/10.1007/s10202-006-0021-8

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